Targeting the vascular interface: beyond crossing the blood-brain barrier.

Abstract

Drug delivery to the CNS has traditionally been evaluated by the ability of carriers to cross the blood-brain barrier (BBB). This barrier-centric view has enabled important progress, but it overlooks a therapeutically significant and design-relevant feature of the neurovascular unit: cerebral endothelial cells and pericytes are active regulators of barrier integrity, vascular tone, immune trafficking, amyloid clearance, and perivascular remodeling. In many neurological disorders, the vascular interface is therefore not merely an obstacle to drug access but also part of the pathological process. This review introduces a vascular-interface-guided framework for CNS delivery system design. We discuss how disease-associated vascular phenotypes, including barrier disruption, immune-endothelial activation, vascular-tone dysregulation, and extracellular-matrix/basal-lamina remodeling, define distinct therapeutic entry points at the luminal endothelial surface, within endothelial trafficking pathways, or in the perivascular niche. We further discuss how receptor identity, ligand affinity and valency, particle size, geometry, surface chemistry, and intracellular sorting determine whether nanocarriers undergo transcytosis, recycling, lysosomal degradation, or endothelial retention. Particular emphasis is placed on endothelial-pericyte crosstalk, pericyte-directed delivery, perivascular depot formation, safety constraints, and translational model selection. Finally, we highlight how computational and predictive modeling could help determine when retention-oriented designs should be prioritized over transcytosis-oriented strategies. We propose that next-generation CNS nanomedicines should be designed by considering therapeutic action at luminal, endothelial, and perivascular sites according to the vascular state of disease, rather than being guided solely by parenchymal delivery.